Sulfuric Acid → 1-Bromo-4-fluoro-5-isopropyl-2-methoxybenzene

Participants

Reaction Conditions

Reaction Steps

A 500 mL dry flask was charged with 2-bromo-5-fluoro-4-isopropylanisole (compound of formula 4, Scheme 3) (24.6 g, 0.1 mol) and dissolved in toluene (80 mL) and THF (80 mL). The resulting solution was flushed with argon, and tri-isopropylborate (32 mL, 0.14 mol) was added. The mixture was cooled to −80° C. Then 10 M n-BuLi in hexanes (12.5 mL, 0.125 mol) was added slowly, maintaining a temperature below −55° C. Thirty minutes after completion of the n-BuLi addition, the reaction was warmed to −35° C. and quenched into 3 M H2SO4 solution (75 mL, 0.225 mol). DIPE (200 mL) was added to the mixture to dilute the organic layer. The mixture was stirred (15 min) and the aqueous layer was cut away. The organic layer was washed with 3.0 M H2SO4 (75 mL). The organic phase was extracted three times with 1M NaOH (200 mL first and then 50 mL and 50 mL). The three NaOH extractions were combined, diluted with 2-propanol (85 mL), and cooled to 15° C. Then the solution was slowly acidified to pH ˜2 using 3 M H2SO4 (70 mL) while maintaining temperature at 15-20° C. The resulting slurry was stirred for 1 hour and then filtered. The filter cake was washed with water (3×30 mL) and dried under an air flow for 1 day. The white crystalline solid was isolated to yield boronic acid of formula 5 (Scheme 3) (19.23 g, 91%): mp 100-102° C.; 1H NMR (CDCl3) δ 1.25 (d, J=6.9 Hz, 6H), 3.17 (sept., J=6.9 Hz, 1H), 3.88 (s, 3H), 5.83 (s, 2H), 6.59 (d, J=12.4 Hz, 1H), 7.72 (d, J=6.6 Hz, 1H).

Provenance & Evidence